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Cheung et al MicroRNAs and nonalcoholic steatohepatitis 1 Supporting Table 1. Transcription factors SOX TRANSCTIPTION FACTOR GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS SOX-3 SOX-4 SOX-5 SOX-6 SOX-8 SOX-9 SOX-11 miR-26b, 30d, 122, 188 miR-361 miR-30d, 188, 203 miR-30d, 126, 145 miR-26b, 122 miR-28 ENSG00000134595 ENSG00000124766 ENSG00000134532 ENSG00000110693 ENSG00000005513 ENSG00000125398 ENSG00000176887 Transcription factor activity Apoptosis, gluconeogenesis, embryogenesis SOX-17 SOX-21 miR-21, 128a, 128b miR-21, 99b miR-224 miR-181b, 199a* miR-224 miR-24, 199a* miR-23a, 23b, 27b, 34a, miR-125b, 128a, 128b, 224 miR-200a miR-21, 23a, 23b, 214 GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS HOX-A1 HOX-A3 HOX-A4 HOX-A5 HOX-A9 miR-92b miR-26b miR-139 miR-26b miR-122 miR-188 miR-92b, 188, 191* miR-188 miR-26b, 188 miR-188 miR-139, 145 miR-122 miR-139 miR-139, 145 ENSG00000105991 ENSG00000105997 ENSG00000197576 ENSG00000106004 ENSG00000078399 Transcription factor activity Target osteopontin (OPN) that modulates angiogenesis, inflammation, apoptosis HOX-C4 HOX-C6 HOX-C9 HOX-C10 HOX-C11 HOX-C13 HOX-D1 HOX-D4 HOX-D9 HOX-D10 HOX-D12 miR-100, 181b miR-16, 23b, 146b miR-128a miR-23b miR-27b, 128a, 128b, miR-199a* miR-16, 99b, 128a, 128b, miR-199a*, 455 miR-23b, 181b miR-27b, 125, 128a, 128b miR-127, 181b miR-23a, 23b miR-16 miR-27b, 128a, 128b, 146b, miR-199a* miR-125b, 146b miR-146b miR-23b miR-146b miR-27b, 181b miR-214 miR-214 miR-16 miR-146b GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS HNF1α HNF1β HNF3β HNF6 miR-214 miR-146b miR-146b miR-23b miR-375, 617 miR-92b miR-26b ENSG00000135100 ENSG00000125798 ENSG00000125798 ENSG00000169856 Liver specific transcription factor HNF3β controls genes in secretion coupling of glucose induced insulin release FOXO1 -> transcription of G6P gluconeogenesis HNF6 interacts selectively with NFAT proteins GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS NFAT4 PBP miR-23a miR-128a, 146b miR-122, 191* ENSG00000072736 ENSG00000125686 Transcription factor activity PPAR binding protein T-cell activation, liver specific Co-activator of PPARs, lipid homeostasis [4] Sox-4-induced apoptosis is accompanied with caspase-1 activation Animal studies have shown that Sox-6 may be an important factor in obesity-related insulin resistance by negatively regulating glucose stimulated insulin secretion from beta-cells [1] ENSG00000164736 ENSG00000125285 HOX TRANSCRIPTION FACTOR HOX-A10 HOX-A11 HOX-A13 HOX-B4 HOX-B5 HOX-B6 HOX-B7 HOX-B8 Glycoprotein OPN is a pro-inflammatory cytokine, adhesion molecule. Chemoattractamt of monocyte in cell mediated immunity. Expressed in hepatic stellate cells and activated macrophage in injured liver [2] ENSG00000153807 ENSG00000005073 ENSG00000106031 ENSG00000182742 ENSG00000120075 ENSG00000108511 ENSG00000120087 ENSG00000120068 LXR ligands inhibit cytokine-induced OPN expression in macrophages [3] ENSG00000198353 ENSG00000197757 ENSG00000180806 ENSG00000180818 ENSG00000123388 ENSG00000123364 ENSG00000128645 ENSG00000170166 ENSG00000128709 ENSG00000128710 ENSG00000170178 HEPATOCYTE NUCLEAR FACTOR OTHERS Cheung et al MicroRNAs and nonalcoholic steatohepatitis 2 Supporting Table 2. Translation and protein processing PROTEIN SYNTEHSIS – EUKARYOTIC TRANSLATION INITIATION FACTOR (eIF) GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS eIF2A1 eIF2A2 eIF2C1 eIF2C2 eIF2C4 eIF3A1 eIF4A1 eIF4A2 miR-122, 188, 191* miR-92b, 122 miR-26b, 92b, 188 miR-188 miR-145 miR-145 miR-122 miR-188, 191* miR-139 miR-92b miR-26b, 145, 361 ENSG00000134001 ENSG00000055332 ENSG00000092847 ENSG00000123908 ENSG00000134698 ENSG00000104131 ENSG00000161960 ENSG00000156976 Eukaryotic translation initiation factor Rate-limiting component of translation initiation Phosphorylation is associated with stress response, causes a reduction in protein synthesis CREB1 CREBBP miR-23a, 23b, 146b miR-146b miR-128a, 128b, 199a* miR-100, 125b, 199a* miR-13b, 27b miR-16, 23b, 146b, 199a* miR-16, 23a, 23b, 27b, miR-128a, 128b miR-16, 139, 214 miR-146b miR-27b, 181b, 128a, 128b, miR-199a* miR-24 miR-16, 200a GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS UBE2-17 UBE2-32 UBE2A UBE2B UBE2D UBE2D3 UBE2E1 UBE2E3 UBE2H UBE2G1 UBE2Q UBE3A RNF144 PJA1 XBP1 EDEM miR-16, 23b miR-23b miR-16 miR-146b miR-23b miR-146b miR-27b, 199a* miR-16, 128a, 128b miR-125b miR-16, 128a miR-27b miR-214 miR-34a miR-125b, 200a, 214 miR-122 miR-139, 145 miR-145 miR-139 miR-122 miR-92b, 145, 188, 191* miR-26b miR-26b - ENSG00000131508 ENSG00000099804 ENSG00000077721 ENSG00000119048 ENSG00000109332 ENSG00000109332 ENSG00000170142 ENSG00000170035 ENSG00000186591 ENSG00000132388 ENSG00000160714 ENSG00000114062 ENSG00000151692 ENSG00000181191 ENSG00000100219 ENSG00000134109 Ubiquitin conjugating enzyme Ubiquitin conjugating enzymes (E2), ubiquitin ligase (E3) and ubiquitin activating enzyme (E1) are involved in the ubiquitin pathway, e.g. ubiquitin proteosome pathway is an intracellular proteolytic mechanism that destroy misfolded or damaged proteins GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS PTP4A3 TP4A2 TMEM59 INSIG2 ATF6 miR-24, 199a*, 222, 455, miR-23a, 23b miR-26b, 34a, 181b , 200a miR-16, 23b miR-16 miR-198, 601 miR-26b, 145 miR-30d, 92b, 223 - ENSG00000184489 ENSG00000184007 ENSG00000116209 ENSG00000125629 ENSG00000118217 Amino acid dephosphorylation Protein dephosphorylation Serine endopeptidase inhibitor activity Respond to sterol depletion Unfolded protein response (UPR) Protein phosphatase activity Protein phosphatase activity Inhibit breakage of peptide bond DNA damage induced protein phosphorylation. Transcription factor induces transcription of genes carrying the ER stress response elements (ERSE) that mediates protein folding eIF4B eIF4E eIF4E3 eIF4G1 eIF4G2 eIF4G3 eIF5A Phosphorylation of eIF2A1 by ER stress activated protein kinase PERK modulates protein synthesis and couples the production of ER client proteins with the organelle’s capacity to fold, process them ENSG00000063046 ENSG00000151247 ENSG00000163412 ENSG00000114867 ENSG00000110321 ENSG00000075151 ENSG00000132502 ENSG00000118260 ENSG00000005339 Protein dimerization activity Transcription factor family (e.g. ATF4), downstream of PERK pathway in UPR (eIF2A1 phosphorylation) PROTEIN DEGRADATION Ubiquitin ligase activity Ubiquitin cycle, protein binding Ubiquitin cycle, ligase activity Protein dimerization activity Response to unfolded protein ER stress induced transcription factor for EDEM ER stress induced protein that regulates disposal of misfolded proteins PROTEIN PROCESSING Cheung et al MicroRNAs and nonalcoholic steatohepatitis 3 Supporting Table 3. Cellular stress, growth and differentiation CELL RESPONSE TO OXIDATIVE STRESS GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS COX6A1 COX7A2 COX8A BLVRB OXSR1 OKL38 miR-99b, miR-423 miR-27b, 127, 128a, 128b miR-99b, 100, 221 miR-128a, 128b miR-23a, 23b, 127 miR-601 miR-198, 361, 563 miR-563, 601 ENSG00000111775 ENSG00000112695 ENSG00000176340 ENSG00000090013 ENSG00000172939 ENSG00000140961 Cytochrome C-oxidase activity Oxidoreductase activity Biliverdin reductase activity Ser/Thr kinase family Negative regulation of cell growth Oxidoreductase activity Regulate downstream kinases in response to stress Oxidative stress induced growth inhibitor GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS PINX1 STARD13 CDC2L5 CGREF1 MYCN MET IRF1 IRF2 miR-24, 34a, 181b miR-125b miR-125b miR-199a* miR-16, 24, 23a, 23b, 125b miR-23b, 125b, 128a, 128b miR-214 miR-188 miR-122 miR-122 miR-145 miR-26b, 145 - ENSG00000104637 ENSG00000133121 ENSG00000065883 ENSG00000138028 ENSG00000134323 ENSG00000105976 ENSG00000125347 ENSG00000168310 Chromosome, telomeric region GTPase activator activity Protein serine/threonine kinase activity (-) regulation of cell proliferation (+) regulation of cell proliferation Protein tyrosine kinase activity Transcription factor activity CDK6 CDK7 CDK10 PIK3CB PIK3R1 PIK3R3 miR-34a, 199a* miR-99b miR-23b miR-27b miR-23b miR-26 miR-122 miR-26b miR-145 ENSG00000105810 ENSG00000134058 ENSG00000185324 ENSG00000051382 ENSG00000145675 ENSG00000117461 Cell cycle arrest (-) regulation of cell growth, differentiation Cell signaling, negative regulation cell cycle Cell proliferation, cytokinesis Ca++ dependent growth/cell cycle inhibitor Transcription factor promoting cell growth/cycle Cell development and proliferation Function not only as regulator of the interferon system, also key transcription factors in the regulation of cell growth and apoptosis via downstream INF inducible effector genes Cyclin dependent kinases play a key role in the different phases of the cell cycle, either promote or prohibit cell cycle progression Catalyzes the conversion of phosphatidylinositol to phosphatidylinositol 3-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 3,4bisphosphate which plays critical role in DNA repair GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) DDEFL1 GDF3 miR-99b miR-125b - ENSGT0000088280 ENSG00000184344 Development and differentiation Growth factory activity LMBRD1 miR-16, 200a ENSG00000168216 Integral to membrane FAD104 AEBP2 MMD MST1R CSF1 miR-23b, 125b, 181a, 214 miR-23b, 146b miR-16, 27b, 30d, 92 miR-24 miR-23a, 27b, 34a, 128b, miR-214 miR-30d, 203, 361, 641 miR-768-5p miR-26b, 122, 145 miR-26b, 139 miR-122, 375 miR-198 miR-122, 188 - ENSG00000075420 ENSG00000139154 ENSG00000108960 ENSG00000164078 ENSG00000184371 (+) regulation of fat cell differentiation Transcription repressor activity Receptor, cytolysis activity Protein tyrosine kinase activity M-CSF receptor binding GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS GJB1 CDH17 miR-21, 23a, 139, 214 - miR-223 ENSG00000169562 ENSG00000079112 Cell-cell signaling; connexon complex Cadherin-17 precursor Gap junction β connexin Maintain cell adhesion CELL GROWTH AND CELL CYCLE Phosphatidylinositol kinase activity Phosphatidylinositol binding Phosphatidylinositol 3 kinase activity CELL DIFFERENTIATION PHYSIOLOGIC FUNCTIONS & IMPLICATIONS TGF-β family, both (+) and (-) regulating cellular differentiation p-53 related protein regulating hepatocyte regeneration Adipocyte differentiation Macrophage differentiation CELL ADHESION Cheung et al MicroRNAs and nonalcoholic steatohepatitis 4 Supporting Table 4. Apoptosis ANTI-APOPTOSIS GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS BCL2L1 BCL2L2 AVEN miR-16, 24, 214 miR-16, 24, 100, 214, 224 miR-200a miR-145 miR-188 miR-92b ENSG00000171552 ENSG00000129473 ENSG00000169857 Apoptosis regulator BCL-X Positive regulation of anti-apoptosis Apoptosis, anti-apoptosis (-) regulation of apoptosis GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS BCL2L7 BCL2L11 BBC3 miR-27b, 125b miR-16, 24, 181, 199a*, 224 miR-24, 125b, 199a*, miR-214, 221, 222 miR-16, 21, 199a*, 200a miR-26b miR-92b miR-122, 145 ENSG00000030110 ENSG00000153094 ENSG00000105327 (+) regulation of apoptosis Induce apoptosis via caspase activation ENSG00000150593 Apoptosis , cell cycle miR-199, 214 miR-125b, 214 miR-16, 34a miR-16, 24, 128a, 128b, miR-181b, 199a*, 423 miR-145 miR-122 miR-188, 375 - ENSG00000076604 ENSG00000118503 ENSG00000180447 ENSG00000181649 Signal transduction (-) regulation of NF-қβ cascade Programmed cell death Pleckstrin homology-like Expression is modulated by cytokines, upregulated in apoptosis and possibly inhibits translation Role in p-53 related pro-apoptotic pathway Deactivation of MAPK and NF-қβ, induces apoptosis Blocks G0-to-S phase transition Induces growth arrest PRO-APOPTOSIS PDCD4 TRAF4 TNFAIP3 GAS1 PHLDA2 Cheung et al MicroRNAs and nonalcoholic steatohepatitis 5 Supporting Table 5. Inflammation ANTI-INFLAMMATORY GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS SOCS2 SOCS4 miR-16, 199a*, 214 miR-16, 23a, 23b, 27b, miR-125b, 128a, 128b, 181b miR-23b, 214 miR-199a* miR-139 miR-188, 191* miR-145 - ENSG00000120833 ENSG00000180008 Intracellular signaling cascade Intracellular signaling cascade Suppress cytokine signaling e.g. JAK/STAT Suppress cytokine signaling ENSG00000114737 ENSG00000171150 ENSG00000113520 (-) regulation signal transduction SOCS family, inhibit JAK-STAT pathways; inhibit macrophage differentiation [5] Th2 immune response CISH1 CISH5 IL4 precursor cytokine receptor activity PRO-INFLAMMATORY – MAP KINASES ACTIVATION GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS MAPKKK1 MAPKKK3 MAPKKKK4 MAPKKK4 MAPK4 MAPKKKK5 MAPKKKK6 MAPK6 MAPKKK7 MAPK7 MAPKKK8 MAPKKK12 MAPK14 PM20 C-JUN k3 CXCR4 miR-23b, 125b, 199a* miR-199a* miR-214 miR-27b, 128a, 128b miR-16, 181b, 214 miR-23b, 128a, 128b miR-199a* miR-214 miR-23a miR-23a, 125b miR-27b, 128a, 128b miR-125b, 128b miR-27b, 128a, 128b, 214 miR-16, 146b miR-145, 188, 191* miR-145 miR-145 miR-92b, 145 miR-139 miR-145 miR-188 - ENSG00000095015 ENSG00000087997 ENSG00000071054 ENSG00000085511 ENSG00000141639 ENSG00000012983 ENSG00000141503 ENSG00000069956 ENSG00000055208 ENSG00000166484 ENSG00000107968 ENSG00000139625 ENSG00000112062 ENSG00000055070 ENSG00000138834 ENSG00000121966 Protein serine/threonine kinase All MAP kinases regulate intracellular signaling, crucial role in immune mediated inflammatory response, cell proliferation, cell differentiation and cell death. 3 main components: JNK, ERK and p38 MAPK activating protein Activation of MAPK Activation of MAPK Activates ERK1/2 pathway Activation of JNK pathway In response to binding its ligand SDF-1 (stromal cell-derived factor-1), CXCR4 triggers the migration and recruitment of immune cells. Potent chemotatic activity for lymphocytes GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS IL2RA IL16 precursor IL17 precursor IL18 precursor IL20 precursor IL22 precursor TNFSF11 CCL16 CCL20 miR-125b, 214 miR-16 miR-128a, 128b miR-23b miR-23b miR-21 miR-122 miR-188, 191* miR-26b miR-617 miR-126 ENSG00000134460 ENSG00000172349 ENSG00000112115 ENSG00000014381 ENSG00000162891 ENSG00000164485 ENSG00000120659 ENSG00000161573 ENSG00000115009 Cytokine receptor activity Th1 immune response TNF receptor binding Chemokine activity, chemoattractant Th1 immune response IL inducible chemokine, lymphocyte and monocyte chemoattractant PRO-INFLAMMATORY – CYTOKINE RECEPTOR ACTIVITY Cheung et al MicroRNAs and nonalcoholic steatohepatitis 6 Supporting Table 5. Inflammation continued PRO-INFLAMMATORY – RAS GTPASE ACTIVITY GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS RAB 1A RAB 2A RAB 5B RAB 5C RAB 6A RAB 7 RAB 9B RAB 10 miR-16 miR-23a, 23b miR-27b, 214 miR-125b miR-27b, 127 miR-146b miR-16, 23a, 23b, 146b, miR-199a* miR-128a, 128b miR-146 miR-27b miR-199a* miR-27b, 125b, 128a, 128b miR-23b miR-23b, 128b miR-16, 23a, 23b, 27b, miR-128a, 128b miR-125b, 199a* miR-100, 146b miR-23b miR-139 miR-26b, 122 miR-139 miR-126 miR-145 miR-139 miR-26b miR-92b, 139 miR-122 - ENSG00000138069 ENSG00000104388 ENSG00000111540 ENSG00000108774 ENSG00000175582 ENSG00000075785 ENSG00000123570 ENSG00000084733 GTPase activity GTPase mediated intracellular signal transduction phagocytosis, cell growth, differentiation and death RAB is a subfamily of RAS GTP-binding protein Subfamily of RAS. RAP 2B may be involved in platelet function RAB 11A RAB 14 RAB 18 RAB 24 RAB 26 RAB 34 RAB 35 RAB 39B RAL A RAP 1B RAP 2B RAS GTPase 1 RAS GTPase 2 ENSG00000103769 ENSG00000119396 ENSG00000099246 ENSG00000169236 ENSG00000167964 ENSG00000109113 ENSG00000111737 ENSG00000155961 ENSG00000006451 ENSG00000127314 ENSG00000181467 ENSG00000145907 ENSG00000138757 Cheung et al MicroRNAs and nonalcoholic steatohepatitis 7 Supporting Table 6. Metabolism PHOSPHOLIPID SYNTHESIS, DEGRADATION AND METABOLISM GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS DGKT DGKZ PL D2 PL Cγ1 LYPLA1 miR-27b miR-214 miR-23b, 214 miR-23a, 23b, 26b, 214 miR-122 miR-203 miR-122 - ENSG00000145214 ENSG00000149091 ENSG00000129219 ENSG00000124181 ENSG00000120992 Diacylglycerol kinase activity PIB5PA miR-146b - ENSG00000185133 Phosphatidylinositol phosphatase Converts DAG → phosphatidic acid (DAG 3phosphate), ↓ precursor for TAG synthesis Hydrolyzes PC → phosphatidic acid and choline PI biphosphate → inositol triphosphate and DAG Hydrolyzes fatty acid ester bond in lyso-glycerophosphatidates → glycerol-phosphatidates and FA Inositol phosphate metabolism Phospholipase D activity Lipid catabolic process Lipid metabolic process CHOLESTEROL SYNTHESIS AND METABOLISM ↓ miRNA miR-26b miR-188, 191* miR-145 miR-145, 191* miR-375, 574 miR-92b, 139 miR-122 miR-122, 145, 188, 375 - IDENTIFIER ENSG00000184792 ENSG00000070882 ENSG00000079156 ENSG00000091039 OSBPL 9 OSBPL 11 NR1H3 NR1H2 NR5A2 HMGCR ACAT SC4MOL ↑ miRNA miR-128b, 146b, 214 miR-181b miR-23a, 23b, 181b, miR-199a*, 200a, 221 miR-125b miR-23b, 27b, 200a, 224 miR-423 miR-423 miR-125b, 224 miR-146b GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS CPT1A PPAR-γ PPAR-α AMPK miR-16, 34a miR-128a, 128b, 146 miR-24, 125b, 214 miR-16, 24, 128a, 128b, miR-181b, 214 miR-23b miR-16, 23b, 199a* - miR-188 miR-188 miR-122 miR-122, 203 miR-26b miR-26b, 145, 188, 191* miR-122 ENSG00000110090 ENSG00000132170 ENSG00000186951 ENSG00000074590 Carnitine O-palmitoyltransferase Nuclear factor Lipid metabolism AMP related protein kinase Fatty acid oxidation, inhibited by malonyl CoA Ligand TZD, increases glucose uptake by tissues Ligands FA/eicosinoid, regulates genes in oxidation FA oxidation via activation of lipase. Inhibits ACC ENSG00000123983 ENSG00000068366 ENSG00000166035 Lipid metabolic process Long chain fatty acid CoA ligase, FA oxidation Triacylglycerol lipase activity TG breakdown to FA GENE OSBPL 2 OSBPL 3 OSBPL 6 OSBPL 8 ENSG00000117859 ENSG00000144909 ENSG00000025434 ENSG00000131408 ENSG00000116833 ENSG00000113161 ENSG00000075239 ENSG00000052802 DESCRIPTION (GO TERM) Steroid metabolic process PHYSIOLOGIC FUNCTIONS & IMPLICATIONS Regulates cholesterol homeostasis. Binds to LXR thus induces transcription of cholesterol-7 alpha hydroxylase, increasing the removal of cholesterol as bile acids Nuclear hormone receptor Oxysterols receptor LXR-beta Cholesterol homeostasis Cholesterol biosynthetic process Acetyl CoA acyltransferase activity C4-methylsterol oxidase activity Activated by oxysterol, regulate cholesterol efflux Rate limiting step of cholesterol synthesis Cholesterol metabolism A SREBP target gene, microsomal enzyme in cholesterol synthesis FATTY ACID OXIDATION ACSL3 ACSL4 LIPC FATTY ACID SYNTHESIS GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS ACC1 ACC2 FASN DGAT1 DGAT2 ULA4 (MAWDBP) SREBP-1 miR-122 miR-122 miR-122 miR-122 miR-122 miR-122 miR-26b, 145, 203 miR-122 ENSG00000132142 ENSG00000076555 ENSG00000169710 ENSG00000185000 ENSG00000062282 ENSG00000035104 ENSG00000072310 Acetyl CoA carboxylase 1 1st committed step of fatty acid synthesis, inactivated when phosphorylated by AMPK Acetyl CoA, malonyl CoA → saturated FA Catalyzes DAG → TAG CREB ACLY miR-16 miR-125b miR-24 miR-146b miR-23a, 23b, 181b, 200a, miR-224 miR-16, 128b, 200a miR-30d, 214 ENSG00000118260 ENSG00000131473 CRE binding protein Metabolic process CB1 CS miR-16, 214, 222 - miR-30d, 361 miR-122 ENSG00000118432 ENSF00000001721 Cannabinoid receptor Citrate synthase Fatty acid biosynthetic process Diacylglycerol acyltransferase Diacylglycerol acyltransferase SREBP transcriptional activation Regulation of transcription Transcriptional activation of FASN, ACC, SCD Hepatic gluconeogenesis and ↓ hepatic lipid Converts acetyl CoA from mitochondria to oxaloacetate & acetyl CoA in the cytoplasm FA synthesis Citric acid cycle, acetyl CoA synthesis Cheung et al MicroRNAs and nonalcoholic steatohepatitis 8 Supporting Table 6. Metabolism continued FATTY ACID DESATURATION AND ELONGATION GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS SCD SCD1 ELOV1 miR-23b, 214 miR-128a, 128b, 199a* miR-122 - ENSG00000099194 ENSG00000099194 ENSG00000066322 Stearoyl CoA desaturase In mitochondria & ER, saturated →unsaturated FA Fatty acid biosynthesis Elongation of long chain FA GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS VLDLR LDLR6 VIGILIN PNPLA7 FABP1 miR-23b, 181b, 199a* miR-16 miR-214 miR-128a, 214 - miR-26b miR-122, 198 miR-203 ENSG00000147852 ENSG00000070018 ENSG00000115677 ENSG00000130653 ENSG00000163586 Receptor activity VLDL (mainly TAG) endocytosis Transcription induced by SREBP, LDL endocytosis Overexpression is seen in ↑ lipid laden macrophage Cleaves FA from PL, also a role in FA oxidation Extract FA from PL GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS ALDOA PRKCB1 PRKCD PRKCQ PFKFB1 PYGL GYG1 (glycogenin) PHKA2 PHKG2 GYS1 GYS2 miR-27b miR-23b miR-34a, 221 miR-21 miR-21 miR-27b, 125b miR-27b, 128b miR-181b, 222 miR-122 miR-145 miR-375 miR-28, 191* miR-145 miR-28, 126, 198, 203 miR-122 - ENSG00000149925 ENSG00000166501 ENSG00000163932 ENSG00000065675 ENSG00000158571 ENSG00000100504 ENSG00000163754 ENSG00000044446 ENSG00000156873 ENSG00000104812 ENSG00000111713 Fructose metabolic process PKC activity PKC activity PKC activity Nucleotide binding Glycogen phosphorylase activity Glycogen biosynthetic process Phosphorylase kinase Phosphorylase kinase Glycogen synthase activity Glycogen synthase activity Glycolysis Activates enzymes in glycolysis and citric acid cycle Glycolysis Glycolysis Gluconeogensis Glycogen metabolism Substrate for elongation by GYS, glycogen synthesis Glycogenosis GENE ↑ miRNA ↓ miRNA IDENTIFIER DESCRIPTION (GO TERM) PHYSIOLOGIC FUNCTIONS & IMPLICATIONS IRS1 IRS4 ISLET1 Myotrophin miR-23a miR-16, 27b, 128a, 128b miR-16, 128a - miR-126, 145 miR-375 ENSG00000169047 ENSG00000133124 ENSG00000016082 ENSG00000100857 Insulin receptor binding Regulate insulin signaling (IRS1-skeletal, IRS2-liver) (IRS4-most recently characterized) Induces transcription of insulin gene Stimulates insulin secretion FATTY ACID AND CHOLESTEROL TRANSPORT Lipid metabolic process Lipid acyl hydrolase Fatty acid-binding protein CARBOHYDRATE METABOLISM Glycogen synthesis INSULIN SIGNALING Energy pathways, transcription factor Regulation of translation Human miRNA gene targets were searched at: microrna.org, sanger.ac.uk, cbio.mskcc.org, PicTar, TargetScan and pubmed literature. Full names for gene abbreviations are available at www.ensembl.org References: 1. Iguchi, H., et al., SOX6 suppresses cyclin D1 promoter activity by interacting with beta -catenin and histone deacetylase 1 and its down-regulation induces pancreatic beta -cell proliferation. J Biol Chem, 2007. 2. Mochida, S., et al., Transgenic mice expressing osteopontin in hepatocytes as a model of autoimmune hepatitis. Biochem Biophys Res Commun, 2004. 317(1): p. 114-20. 3. Ogawa, D., et al., Liver x receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways. Circ Res, 2005. 96(7): p. e59-67. 4. Jia, Y., et al., Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver. J Biol Chem, 2004. 279(23): p. 24427-34. 5. Starr, R., et al., A family of cytokine-inducible inhibitors of signalling. Nature, 1997. 387(6636): p. 917-21.
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